This proposal characterizes CD4 independent strains of SIV with the goal of developing novel envelope based vaccines. In addition, we will characterize the humoral immune response generated in macaques immunized or infected with both CD4 dependent and CD4 independent viruses. Methods have been developed to analyze antibody blocking of envelope gpl20 with either the CD4 or CCR5 receptor molecules. We then propose to use the information gained from identification of determinants of CD4 independence in combination with that gained from immunization and infection studies to generate a vaccine that will more effectively expose the highly conserved and functionally critical coreceptor binding site. Finally, conformationally intact coreceptor molecules will be purified and mixed with these CD4 independent envelope proteins to generate "triggered" envelopes that will also expose critical determinants of the gp41 subunit for immune recognition and hopefully elicit a productive neutralizing antibody response.